Monoaminergic (MA) neurons in the brainstem send widespread projections to the cerebral cortex and give rise to specific patterns of innervation in different cortical areas. There is new evidence that the regional differences are most highly differentiated in the primate. The purpose of this study is to characterize in primate neocortex four anatomic features of the MA projections that are important determinants of their function: the pattern of terminal innervation, the topographic organization of neurons that project to different cortical areas, the ultrastructural features of axon terminals, and the identification of cortical neurons that are the targets of the MA axons. In different cortical areas, the innervation pattern of MA axons visualized by immunocytochemistry (ICC) will be analyzed quantitatively in terms of axon density, length and orientation. The topographic organization of raphe neurons will be studied by retrograde transport of fluorescent dyes from different cortical areas combined with ICC for identification of serotonergic and other cell types. EM ICC will be employed to determine the ultrastructural features of contacts between MA axons and cortical neurons. The target cells of MA axons will be identified employing a dual label technique in which particular sets of cortical neurons are visualized by retrograde transport of ICC. For subsequent neurophysiologic analysis of the effect of MA axons upon neuronal activity, an experimental model will be developed using neurotoxic ablation of MA axons in localized islands of cortex. These neuroanatomic studies should contribute new information, that is particularly relevant for man, concerning the functional organization of the MA neurons. These neurons, which are affected by widely used drugs, have been implicated in the control of sleep and attention, and abnormalities of these projections may results in neurologic and psychiatric disorders, especially depression, mania, and dementia.